ABSTRACT There is an unmet need for novel approaches to cancer research, including improved model systems. Pet dogs are among the most promising natural models for translational cancer research?. They share our environment and develop cancers with clear clinical, histological, and genomic similarities to human cancer. We propose to use new genomic technology and a direct-to-dog-owner approach to overcome existing limitations of the canine model. To accomplish this, we will use new liquid biopsy technology, which makes it possible to sequence ?tumor exomes in circulating cell-free DNA from a blood sample, and thus achieve deeper understanding of tumor genomics without invasive biopsies. The power of these minimally invasive sampling technologies is greatest in application to very large sets of clinical samples. Family dogs, whose environments are shared with humans and for which tumor genomics are similar to human cancers, offer an unparalleled model in which to assemble clinical sets of size sufficient both to confirm the relevance of known genetic pathways, and to identify new ones. We propose to combine the power of cell-free DNA sequencing, ?the enthusiasm of citizen-scientist pet owners, and the clinical experience of veterinarians. We will create a research portal for collection of information on diagnosis, treatment, and outcome for thousands of dogs with cancer, as well as their environment and lifestyle. W?e will also develop new computational methodologies to identify genomic similarities between canine and human cancers. Comparison of these canine and human mutational profiles will enable matching of canine cancer subtypes with human cancer subtypes based on genetic pathways, facilitating canine trials to advance human clinical studies. We aim to: Aim 1. ?Develop software to Identify canine models for human cancers using genomic data and comprehensive, histology-blind analysis approach. Aim 2. Develop and optimize ?cell-free DNA sampling and sequencing methods in dogs, including ultra-low-pass whole genome sequencing and whole exome sequencing. Aim 3. Implement a ?direct-to-dog-owner smartphone app to collect and validate detailed clinical, and environmental data, paired with blood samples, for thousands of dogs. By combining the power of genome sequencing and new liquid biopsy technology with the opportunity to collect large sets of samples from a species whose cancers are genomically reflective of those in humans, our project? will? transform? the scale and scope of translational cancer research and precision medicine.